HEATR1 Promotes Glioblastoma Cell Proliferation, Migration, and Invasion Through Regulation of Nrf2

Background: HEAT repeat-containing protein 1 (HEATR1) has been reported to play key roles in tumor progression, but its expression patterns and functional significance in glioblastoma (GBM), particularly in relation to the nuclear factor erythroid 2-related factor 2 (Nrf2) regulatory pathway, remain poorly understood. Therefore, this study aimed to investigate the expression profile of HEATR1 in GBM and to elucidate its functional role and underlying molecular mechanisms, with a specific focus on its regulatory relationship with Nrf2. Methods: Bioinformatics analyses using GEPIA2, cBioPortal, and the Human Protein Atlas were employed to evaluate HEATR1 expression and its correlation with Nrf2 in GBM. Functional assays, including shRNA-mediated gene silencing, Nrf2 overexpression, Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and Transwell invasion, were performed in U87 and U251 cell lines. Quantitative real-time PCR (qRT-PCR) was employed to assess mRNA levels, and protein abundance was determined using Western blot analysis. Results: Knockdown-mediated silencing of HEATR1 expression led to a pronounced reduction in the proliferative, migratory, and invasive abilities of GBM cells. From a mechanistic perspective, HEATR1 functioned as a positive regulator of Nrf2, enhancing its expression at both transcriptional and translational levels; however, the regulatory relationship appeared to be unidirectional, since alterations in Nrf2 expression did not exert feedback effects on HEATR1 expression. Experimental rescue analysis revealed that elevating Nrf2 expression could partially mitigate the inhibitory consequences of HEATR1 depletion on the proliferative, migratory, and invasive properties of GBM cells. Conclusion: HEATR1 promotes glioblastoma progression by upregulating Nrf2, thereby enhancing cellular proliferation, migration, and invasion. The HEATR1–Nrf2 axis may represent a promising therapeutic target in GBM.